Immunomodulatory properties of CD38 antibodies and their effect on anticancer efficacy in multiple myeloma
Kamlesh Bisht1, Taro Fukao1, Marielle Chiron2
1Sanofi Oncology, Cambridge, Massachusetts, USA.
Background:
CD38 has been established as an important therapeutic target for multiple myeloma (MM), for which two CD38 antibodies are currently approved-daratumumab and isatuximab. CD38 is an ectoenzyme that degrades NAD and its precursors and is involved in the production of adenosine and other metabolites.
Aim:
Among the various mechanisms by which CD38 antibodies can induce MM cell death is immunomodulation, including multiple pathways for CD38-mediated T-cell activation. Patients who respond to anti-CD38 targeting treatment experience more marked changes in T-cell expansion, activity, and clonality than nonresponders.
Implications:
Resistance mechanisms that undermine the immunomodulatory effects of CD38-targeting therapies can be tumor intrinsic, such as the downregulation of CD38 surface expression and expression of complement inhibitor proteins, and immune microenvironment-related, such as changes to the natural killer (NK) cell numbers and function in the bone marrow niche. There are numerous strategies to overcome this resistance, which include identifying and targeting other therapeutic targets involved in, for example, adenosine production, the activation of NK cells or monocytes through immunomodulatory drugs and their combination with elotuzumab, or with bispecific T-cell engagers.
Insights
CD38 antibodies are effective against multiple myeloma (MM) by activating T-cells. Overcoming resistance involves targeting CD38 downregulation and immune microenvironment changes for better treatment outcomes.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- CD38 is a validated therapeutic target for multiple myeloma (MM).
- Approved CD38 antibodies include daratumumab and isatuximab.
- CD38's enzymatic activity impacts NAD and adenosine metabolism.
Purpose of the Study:
- To explore the immunomodulatory mechanisms of CD38 antibodies in MM.
- To identify resistance pathways to CD38-targeting therapies.
- To propose strategies for overcoming therapeutic resistance.
Main Methods:
- Analysis of T-cell responses in MM patients treated with CD38 antibodies.
- Investigation of intrinsic and microenvironment-related resistance mechanisms.
- Review of combination strategies to enhance CD38-targeted therapy.
Main Results:
- CD38 antibody treatment leads to significant T-cell expansion and activation in responders.
- Tumor-intrinsic factors (e.g., CD38 downregulation) and immune microenvironment changes contribute to resistance.
- Specific resistance mechanisms include altered NK cell function and complement inhibition.
Conclusions:
- CD38 antibodies exert therapeutic effects through T-cell activation.
- Understanding resistance mechanisms is crucial for optimizing MM treatment.
- Combination therapies targeting adenosine pathways, NK cells, or using bispecific T-cell engagers show promise for overcoming resistance.
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